Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC) (ATTACC)
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| ClinicalTrials.gov Identifier: NCT04372589 |
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Recruitment Status :
Completed
First Posted : May 4, 2020
Last Update Posted : July 27, 2021
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Sponsor:
University of Manitoba
Collaborator:
University Health Network, Toronto
Information provided by (Responsible Party):
University of Manitoba
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Brief Summary:
Endothelial injury as a consequence of SARS-CoV-2 infection leads to a dysregulated host inflammatory response and activation of coagulation pathways. Macro- and micro-vascular thrombosis may contribute to morbidity, organ failure, and death. Therapeutic anticoagulation with heparin may improve clinical outcomes in patients with COVID-19 through anti-thrombotic, anti-inflammatory, and anti-viral activities of heparins. This pragmatic, Bayesian adaptive randomized controlled trial will determine whether therapeutic anticoagulation with heparin (subcutaneous low molecular weight heparin or intravenous unfractionated heparin) versus usual care reduces the need for intubation or death in hospitalized patients with COVID-19. The trial uses an adaptive design which was chosen to overcome limitations in available data to inform a priori estimation of event rates and possible effect sizes. The adaptive design also includes response-adaptive randomization based on baseline D-dimer level, probing for differential efficacy across subgroups defined based on initial D-dimer level. This Bayesian adaptive randomized trial will stop at a conclusion 1) when the posterior probability that the proportional odds ratio is greater than 1.0 reaches 99% (definition of benefit); 2) when the posterior probability that the proportional odds ratio is greater than 1.2 is less than 10% (definition of futility) or; 3) when the posterior probability that the proportional odds ratio is less than 1.0 is greater than 90% (definition of harm). The trial will enroll a maximum of 3,000 patients, although in many simulations the trial may require fewer patients. The trial is strategically aligned with the international REMAP-CAP/COVID platform trial to accelerate evidence generation.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| COVID-19 Pneumonia | Drug: Heparin | Phase 2 Phase 3 |
This is a prospective, open-label, multicentre, Bayesian adaptive randomized clinical trial to establish whether therapeutic-dose parenteral anticoagulation improves outcomes for patients hospitalized with COVID-19 (e.g., reduces intubation or mortality). Participants will be randomized either to the investigational arm (therapeutic anticoagulation with heparin for 14 days or until "recovery" [defined as hospital discharge or liberation from supplemental oxygen if initially required], whichever comes first), or to the control arm (usual care, including thromboprophylactic dose anticoagulation according to local practice).
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 1200 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention Model Description: | Pragmatic, Bayesian adaptive randomized controlled trial |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC), in Collaboration With Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) |
| Actual Study Start Date : | May 20, 2020 |
| Actual Primary Completion Date : | May 17, 2021 |
| Actual Study Completion Date : | May 17, 2021 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Experimental: Investigational arm
Participants randomized to the investigational arm will receive therapeutic anticoagulation for 14 days (or until hospital discharge or liberation from supplemental oxygen >24 hours if previously required, whichever comes first) with heparin, with preference for subcutaneous low molecular weight heparin (enoxaparin preferred, although dalteparin or tinzaparin are also acceptable, as available) if no contraindication is present; alternatively, intravenous unfractionated heparin infusion may be used.
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Drug: Heparin
Low molecular weight heparin (LMWH) Preferred therapeutic anticoagulant is enoxaparin. Generally regimens: 1.5 mg/kg subcutaneous once daily or 1 mg/kg subcutaneous twice daily. Alternatively, other subcutaneous LMWH used, including tinzaparin (175 anti-Xa IU/kg subcutaneous once daily) or dalteparin (200 IU/kg subcutaneous once daily or 100 IU/kg subcutaneous twice a day). Unfractionated heparin (UFH) Commenced, administered, and monitored according to local hospital policy, and guidelines that are used for the treatment of venous thromboembolism (i.e. not for acute coronary syndrome). Intravenous infusion of UFH is according to total body weight and pragmatically adjusted according to local institutional policy to achieve an activated partial thromboplastin time (aPTT) of 1.5-2.5x the reference value. If UFH is used, the availability of a local hospital policy that has specifies an aPTT target in this range or an anti-Xa value is a requirement. |
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No Intervention: Control arm
Participants will receive usual care of thromboprophylactic dose anticoagulation according to local practice.
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Primary Outcome Measures :
- Mortality and days free of organ support [ Time Frame: 21 days ]The primary endpoint in the trial is days alive and free of organ support at day 21. This endpoint is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ support is defined as receipt of invasive or non-invasive mechanical ventilation, high flow nasal oxygen (>30 L/min), vasopressor therapy, or ECMO support. Death at any time (including beyond 21 days) during the index hospital stay is assigned the worst possible score of -1.
Secondary Outcome Measures :
- Arterial and venous thrombotic conditions [ Time Frame: 28 days and 90 days ]A composite endpoint of death, deep vein thrombosis, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke collected during hospitalization or at 28 days and 90 days after enrollment (whichever is earlier).
- Intubation and mortality [ Time Frame: 30 days ]Ordered categorical endpoint with three possible outcomes based on the worst status of each patient through day 30 following randomization: no invasive mechanical ventilation, invasive mechanical ventilation, or death.
- All-cause mortality [ Time Frame: 28 days and 90 days ]
- Intubation [ Time Frame: 30 days ]Invasive mechanical ventilation.
- Hospital-free days [ Time Frame: 28 days ]Days alive outside of the hospital through 28 days following randomization.
- Ventilator-free days [ Time Frame: 28 days ]Days alive not on a ventilator assessed at 28 days following randomization.
- Myocardial infarction [ Time Frame: 28 days and 90 days ]
- Ischaemic stroke [ Time Frame: 28 days and 90 days ]
- Venous thromboembolism [ Time Frame: 28 days and 90 days ]Symptomatic proximal venous thromboembolism (DVT or PE).
- Vasopressor-free days [ Time Frame: 28 days ]Days alive not on a vasopressor assessed at 28 days following randomization.
- Renal replacement free days [ Time Frame: 28 days ]Days alive not on renal replacement assessed at 28 days following randomization.
- Hospital re-admission [ Time Frame: 28 days ]Hospital re-admission within 28 days.
- Acute kidney injury [ Time Frame: Duration of study ]As defined by KDIGO criteria.
- Systemic arterial thrombosis or embolism [ Time Frame: 28 days and 90 days ]
- ECMO support [ Time Frame: Duration of study ]Use of extracorporeal membrane oxygenation (ECMO) support.
- Mechanical circuit thrombosis [ Time Frame: Duration of study ]Dialysis or ECMO.
- WHO ordinal scale [ Time Frame: 28 days ]Peak scale over 28 days, scale at 14 days, and proportion with improvement by at least 2 categories compared to enrollment, at 28 days.
- Major bleeding [ Time Frame: Intervention period (maximum 14 days) ]As defined by the International Society on Thrombosis and Haemostasis (ISTH).
- Heparin-induced thrombocytopenia (HIT) [ Time Frame: Intervention period (maximum 14 days) ]Laboratory-confirmed.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
1. Patients ≥18 years of age providing (possibly through a substitute decision maker) informed consent who require hospitalization anticipated to last ≥72 hours, for microbiologically-confirmed COVID-19, enrolled < 72 hours of hospital admission or of COVID-19 confirmation
• If the patient is already hospitalized and the COVID-19 diagnosis is due to an outbreak or an incidental finding, then enrollment can occur within 72 hours of a clinical syndrome attributable to COVID-19 that requires continued hospitalization (e.g. new or worsening oxygen requirements or acute kidney injury) which is further anticipated to extend the hospital admission by an additional 72 hours from randomization.
Exclusion Criteria:
- Patients admitted to an ICU AND receiving organ support (i.e. high flow nasal oxygen, receiving non-invasive or invasive mechanical ventilation, or are requiring vasopressor/inotrope)
- Patients for whom the intent is to not use pharmacologic thromboprophylaxis
- Active bleeding
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Risk factors for bleeding, including:
- intracranial surgery or stroke within 3 months;
- history of intracerebral arteriovenous malformation;
- cerebral aneurysm or mass lesions of the central nervous system;
- intracranial malignancy
- history of intracranial bleeding
- history of bleeding diatheses (e.g., hemophilia)
- history of gastrointestinal bleeding within previous 3 months
- thrombolysis within the previous 7 days
- presence of an epidural or spinal catheter
- recent major surgery <14 days
- uncontrolled hypertension (sBP >200 mmHg, dBP >120 mmHg)
- other physician-perceived contraindications to anticoagulation
- Platelet count <50 x10^9/L, INR >2.0, or baseline aPTT >50 (if available per SOC testing)
- Hemoglobin <80 g/L (to minimize the likelihood of requiring red blood cell transfusion if potential bleeding were to occur)
- Acute or subacute bacterial endocarditis
- History of heparin induced thrombocytopenia (HIT) or other heparin allergy including hypersensitivity
- Current use of dual antiplatelet therapy
- Patients with an independent indication for therapeutic anticoagulation
- Patients in whom imminent demise is anticipated and there is no commitment to active ongoing intervention
- Anticipated transfer to another hospital that is not a study site within 72 hours
- Enrollment in other trials related to anticoagulation or antiplatelet therapy
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04372589
Locations
Show 60 study locations
Sponsors and Collaborators
University of Manitoba
University Health Network, Toronto
Investigators
| Principal Investigator: | Patrick R. Lawler, MD, MPH | Peter Munk Cardiac Centre/University Health Network | |
| Principal Investigator: | Ewan C. Goligher, MD, PhD | University Health Network, Toronto | |
| Principal Investigator: | Ryan Zarychanski, MD, MSc | University of Manitoba |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | University of Manitoba |
| ClinicalTrials.gov Identifier: | NCT04372589 |
| Other Study ID Numbers: |
ATTACC OZM-113 ( Other Identifier: Ozmosis Research Inc ) |
| First Posted: | May 4, 2020 Key Record Dates |
| Last Update Posted: | July 27, 2021 |
| Last Verified: | January 2021 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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COVID-19 Pneumonia, Viral Pneumonia Respiratory Tract Infections Infections Virus Diseases Coronavirus Infections Coronaviridae Infections Nidovirales Infections |
RNA Virus Infections Lung Diseases Respiratory Tract Diseases Heparin Anticoagulants Fibrinolytic Agents Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action |